ABSTRACT The economic burden of chronic pain in the U.S. is staggering. In the cases of medically refractory chronic neuropathic pain, neuromodulation, such as spinal cord stimulation (SCS) and/or dorsal root ganglion (DRG) stimulation, is a non-opioid-based option. Though neuromodulation is typically electrical, here we examine an alternative with pulsed high-intensity focused ultrasound (HIFU). Delivering HIFU at lower doses in a pulsed fashion has been shown to temporarily block compound action potentials in pre-clinical models. Though the blockage lasts seconds to minutes, our lab has shown that using either invasive or external HIFU, the anti- nociceptive responses induced by the thermal energy last for days in multiple rodent pain models. Further, the antinociceptive effects of external pulsed HIFU on the DRG and its exiting nerve roots (ENRs) are dose dependent and have similar effects with repeated treatments in rodent models. Postmortem histology reveals no damage to nerves or ganglion cells after treatment. Thus, this is truly a neuromodulatory strategy rather than an ablative one. Currently, our device lacks the ability to visualize the target and directly monitor thermal effects at the target. In this project, we will develop a fully external HIFU system which can visualize the target, monitor thermal energy delivery and provide treatment for chronic neuropathic pain. Specifically, we aim to develop a state-of-the-art directional noninvasive application-specific ?soft-focused? HIFU device that is able to treat chronic neuropathic pain in the clinic within minutes. As we aim for this procedure to be done in the clinic under local anesthetic within minutes and to be completely external, we will augment our existing device using a clinical diagnostic ultrasound imaging probe which can be used for image guidance, targeting, and monitoring the therapy using quantitative ultrasound imaging techniques. This capability will be integrated into our external HIFU device via an iterative process of simulation modeling, bench testing and animal work in a swine neuropathic pain model. Phase 2 studies will be developed to culminate in a pilot first-in-man trial.